The etiology of insulin dependent diabetes mellitus in humans seems to entail an interaction between a susceptible genotype and an environmental stress. The recessive mutation diabetes in the mouse is consequently of interest as a model system for understanding such interactions. The diabetes gene itself does not determine whether a mild or a several diabetes syndrome will result; rather, its expression creates a diabetogenic environment that demands an increased insulin supply. The response to this stress is determined by other genetic factors in the inbred strain background. Thus, diabetes gene expression in certain inbred strains (C57BL/KsJ, CBA/J) is characterized by an abortive attempt to increase insulin supply, with insulinopenia, beta cell necrosis, and severe diabetes resulting. On the contrary, in other inbred strains (C57BL/6J, 129/J), the diabetogenic stress is met by an enhanced insulin secretion that is sustained indefinitely. An understanding of the action of modifing genes that change the course of murine diabetes from a severe juvenile-onset type to a mild maturity-onset type would be an important contribution to the understanding of diabetes in man. The objectives of the current research are to elucidate the site and mechanism of action of the db gene, and to understand how heredity and environment can interact in the diabetes-susceptible inbred mouse strains to produce beta cell necrosis. Feeding mutant mice a high protein-no carbohydrate diet allows full expression of the db gene while at the same time prevents beta cell necrosis and diabetes development in the suscetible C57BL/KsJ strain. We shall screen monolayer cultures of pancreatic islet cells from normal and mutant mice to test for expression of intrinsic genetic defect. We will use in vivo and in vitro tests to show how dietary carbohydrate might interact with C57BL/KsJ and CBA/J diabetes-susceptible genomes to culminate in beta cell necrosis and severe diabetes.